Researchers at the University of Pennsylvania’s Perelman School of Medicine and Penn Medicine’s Abramson Cancer Centre have discovered that a simple dietary supplement might provide a novel means of improving CAR T cell function.
Although the approach needs to be tested in clinical trials, the preliminary research, which was presented at the 66th American Society of Haematology (ASH) Annual Meeting and Exposition (Abstract 4), points to a potentially cost-effective method of improving CAR T cell activity and cancer-fighting capabilities.
Developed at Penn Medicine, CAR T cell therapy is a customized therapeutic strategy that rewires patients’ immune systems to eradicate their cancer.
Co-lead author Shan Liu, PhD, a postdoctoral fellow who presented the study at ASH, stated, “CAR T cell therapy has been effectively used to treat thousands of patients with blood malignancies, but it still does not work for everyone.” “By targeting T cells through food instead of additional genetic engineering, we took an unconventional strategy to improve CAR T cell treatment.”
Liu and Puneeth Guruprasad, PhD, who is currently a medical student at the Perelman School of Medicine and received his PhD at Penn, co-led the study. The lead authors were guided by co-senior authors Maayan Levy, PhD, an assistant professor of microbiology, and Marco Ruella, MD, an assistant professor of haematology-oncology, a researcher with the Center for Cellular Immunotherapies, and the scientific director of Penn Medicine’s lymphoma program.
Using a mouse model of diffuse-large B-cell lymphoma, the researchers first examined the impact of various diets, including ketogenic, high-fiber, high-fat, high-protein, high-cholesterol, and a control diet, on the tumour-fighting potential of CAR T cells. When compared to all other diets, they discovered that mice on a ketogenic diet had better tumour management and survival rates. Subsequent research revealed that a major mediator of this impact was elevated levels of beta-hydroxybutyrate (BHB), a metabolite the liver produces in response to a ketogenic diet.
The study expands on earlier research by Levy’s group, which discovered that BHB significantly inhibited colorectal tumour growth in laboratory tests.
Guruprasad stated, “We think that BHB is a better fuel source for CAR T cells than the normal carbohydrates in human bodies, such as glucose.” Therefore, raising the body’s BHB levels increases the ability of CAR T cells to eliminate cancer cells.
In laboratory models of human cancer (on a normal diet), the study team then tried a BHB supplement in conjunction with CAR T cell therapy. The results showed that the BHB supplement completely eradicated the cancer in the great majority of mice and increased the activation and growth of CAR T cells. The team evaluated blood samples from patients who had just had CAR T cell therapy to determine whether BHB, which is found in our bodies naturally at different levels, had a comparable effect in people.
They discovered that higher BHB levels were linked to better CAR T cell expansion in patients. Similar alterations in the way normal T cells produced energy following exposure to BHB were also observed when they examined the T cells of healthy participants who received a BHB supplement.
Past studies across several cancer types have looked at the impact of dietary interventions, such as a high-fiber diet, on the response to cancer immunotherapy, however the mechanism behind the BHB effect in this study appears to stem from metabolic changes in the blood, rather than via the gut microbiome, as in the case of a high-fiber diet.
The theory that BHB supplementation could improve response to CAR T cell therapy is being tested in a Phase I clinical trial at Penn Medicine’s Abramson Cancer Center.
“We are talking about an intervention that has low toxicity potential and is reasonably inexpensive,” Levy stated. “I am excited to consider how a relatively straightforward strategy like this could be paired with dietary treatments or other, more conventional approaches, to boost the anti-cancer benefit, if the clinical trial data proves out.”
Elise Chong, MD, an assistant professor of Haematology-Oncology and the clinical trials primary investigator, will shortly start accepting patients with relapsed or refractory large B-cell lymphoma who are undergoing treatment with commercially available anti-CD19 CAR T cell therapy.
“I am excited to see this research go from the lab bench to translational studies and now to a clinical trial,” Ruella said. “As a doctor and scientist, I share my patients’ excitement for possible new techniques to better treat their cancer.” “But, we want to stress that, at this time, the research is still early, and until we have conclusive clinical proof, we are not providing any dietary or supplement advice to patients based on this study.”
-NSH Digidesk
